In this study, we summarized the data of 21 Chinese patients with VS treated at Sun Yat-sen University Cancer Center. To our knowledge, this is the largest cohort to date from single institution, allowing for the calculation of survival rates. The 3-year survival rate was 92.3% for patients receiving wide resection at initial diagnosis, and 50.0% for those referred with recurrent disease. Although the difference merely approached statistical significance, it clearly indicated the importance of wide resection in the initial management of VS.
VS is a heterogeneous disease with several histological subtypes [3, 4]. In our institution, VS accounted for 3.9% of contemporaneous vulvar malignancies. Epithelioid sarcoma was the most common subtype in our cohort (42.9%), followed by leiomyosarcoma (19.0%) and dermatofibrosarcoma protuberans (19.0%). The onset age covered a wide range in patients with epithelioid sarcoma and dermatofibrosarcoma protuberans, while it seemed to be younger for patients with leiomyosarcoma and rhabdomyosarcoma. Due to the diversity of its histological subtypes, pathologists usually encounter difficulty in diagnosis, necessitating additional diagnostic measures [13, 14]. In our study, all patients had IHC examination with panels of multiple biological markers. The expression profile for each histological subtype was generally the same to those reported in previous literatures.
FISH was performed in 6 patients and only one patient with dermatofibrosarcoma protuberans showed positive signals for COL1A1-PDGFB fusion. Dermatofibrosarcoma protuberans is a relatively less aggressive tumor featured by high incidence of local recurrence and low risk of metastases [15]. A recent case report by Neff et al. described a case with vulvar massive dermatofibrosarcoma protuberans [16]. Although the tumor had invaded the deep inguinal-femoral spaces, the surrounding lymph nodes were negative. However, in our cohort, No.2 patient displayed a different disease course, in which multiple inguinal node metastases occurred despite relatively small tumor (3×4 cm). The pathological graphics of this patient are showed in Figure 2. This patient finally died of the disease although extensive resection and adjuvant chemoradiotherapy were accomplished, suggesting the importance of evaluation on regional nodes and the necessity of additional therapeutic approaches.
COL1A1-PDGFB gene rearrangements can be detected in majority of dermatofibrosarcoma protuberans [17]. Jahanseir et al. reported a series of 11 patients with vulvar dermatofibrosarcoma protuberans, of whom 9 were found to have COL1A1-PDGFB gene rearrangement [18]. The COL1A1-PDGFB fusion produces a chimeric protein, which can stimulate cell proliferation through maintaining the activity of platelet-derived growth factor receptor [19]. This molecular mechanism relies on the function of downstream tyrosine kinases which can be utilized as therapeutic target [20]. Notedly in our study, the patient showing positive for COL1A1-PDGFB fusion also had a history of breast and endometrial cancers, suggesting an important role of COL1A1-PDGFB fusion in the course of tumorigenesis. Thus, for patients with suspected vulvar dermatofibrosarcoma protuberans, FISH should be recommended not only for diagnostic purposes but also for potential targeted therapy.
Radical resection with enough margin is a guarantee of oncological control for VS [6, 21]. Unfortunately, all patients in our cohort were initially treated at community and none of them received wide resection at primary surgery. For patients who were timely referred to our gynecological oncologists, extended resection resulted in favorable outcomes at minor costs. Most of these patients were discharged within one week after operation and there were no severe complications observed. Only 3 patients relapsed during a median follow-up period of 36 months.
The No.1 patient is a special case who was initially misdiagnosed as Bartholin cyst and treated by cystectomy. She was referred to us with revised pathological diagnosis of well-differentiated leiomyosarcoma and then received extended resection with negative margins. Four years later she got relapse at vulva and received the third resection. Again, four years later she got the second relapse simultaneously at vulva and lumbar vertebra. Her disease was evaluated as progress after 3 cycles of chemotherapy (ifosfamide+cisplatin+doxorubicin). Afterwards, she sequentially received the fourth vulvar surgery, radiotherapy to the lumbar, and immunotherapy using cytokine induced killer cells. She had survived with disease more than 5 years after the last treatment and the disease was evaluated as stable in a most recent follow-up (March 2020). The treatment course of this patient implied high relapse potential of leiomyosarcoma and underlined the importance of initial surgery. Furthermore, multidisciplinary cooperation might be a solution for metastatic diseases.
There are very few data on recurrent VS in the literature. In our cohort, 8 patients were referred with at least one recurrence, for whom the treatment became more challenging. The surgeries for them were more extensive in which adjacent structure resection and flap transplantation were usually required. In addition, chemoradiotherapy was also planned in 7 patients. The surgical morbidity was high, and the hospital stays were obviously longer than those referred at initial diagnosis. Nevertheless, the outcomes seemed to be encouraging since there were 3 patients achieved long-term survival without disease (No.3, 7, 14). Therefore, we believe that the recurrent VS remains potentially curable and aggressive treatments should be planned especially for patients with local recurrence.
The role of lymphadenectomy in the treatment for VS is unclear [12]. Theoretically, sarcomas spread mainly by hematogenous pathway and lymphadenectomy can be omitted unless there are clinically suspected nodes [22]. However, the rate of nodal metastasis seemed to be higher in some subtypes of sarcoma, such as epithelioid sarcoma and rhabdomyosarcoma [23]. In our cohort 9 patients had lymphadenectomy and 3 of them had positive findings. However, we could not confirm a therapeutic benefit of lymphadenectomy as all patients showing lymph node metastases had relapsed in a short time and finally died of disease. The necessity of lymphadenectomy may be determined by histological subtype and imaging examination. Given the high morbidity associated with lymphadenectomy, sentinel lymph node biopsy may serve as an alternative when indicated [24].
The role of chemoradiation as adjuvant treatment for VS is also unclear. Postoperative radiotherapy had been found to be beneficial for a variety of sarcomas [25]. Evidence from sarcoma of extremities suggested an improvement of recurrence-free survival in patients receiving postoperative chemotherapy [26]. The experience from our cohort showed that these adjuvant therapies might be beneficial in specific situations.
As a retrospective study of rare disease, our analysis was limited by its small sample size. There might also be unaware heterogeneity between different histological subtypes. Besides, nearly half of our patients were recurrent cases and the adjuvant treatments were highly individualized, which weakened the capacity to analyze the prognostic impact of single intervention. Thus, the results of this study should be interpreted with prudence.
In conclusion, VS is a rare malignance with heterogeneous histological types. IHC and FISH are important diagnostic measures. Although most patients were initially treated with inadequate surgery, additional extended resection by gynecological oncologists provided favorable outcomes. For recurrent cases, there remained some opportunities to survive if aggressive treatments were carried out. The therapeutic benefits of lymphadenectomy and chemoradiotherapy remains to be determined in further investigations.